Transcriptional variations at perilesional site in vitiligo patients: probably a fight for cell-survival.

Exploration of gene expression variations is a potential source to unravel biological pathways involved in pathological changes in body and understand the mechanism underneath. Vitiligo patients were explored for gene expression changes transcriptionally at perilesional site in comparison to normal site of same patients for melanogenesis pathway (TYR, DCT & TYRP1) cell adhesion (MMPs & TIMP1), cell survival (BCL2 & BAX1) as well as proliferation, migration & development (SOX9, SOX10 & MITF) regulatory system, using skin biopsy samples. Results were also compared with changes in gene expression for melanocytes under stress after hydrogen peroxide treatment in-vitro. Gene amplification was carried out via real time PCR. We found increased expression of proliferation, migration & development regulatory genes as well as melanogenesis pathway genes at perilesional site of patients. In-vitro study also supports induced MITF expression and disturbed melanogenesis in melanocytes under stress. Expression level ratio of cell survival regulatory genes' (BCL2/BAX1) as well as cell adhesion regulatory genes (MMPs/TIMP1) was observed upregulated at patient's perilesional site however downregulated in hydrogen peroxide treated melanocytes in-vitro. Observed upregulated gene expression at perilesional site of patients may be via positive feedback loop in response to stress to increase cell tolerance power to survive against adverse conditions. Gene expression analysis suggests better cell survival and proliferation potential at perilesional site in vitiligo patients. It seems in-vivo conditions/growth factors supports cells to fight for survival to accommodate stressed conditions.

Melanocyte Density in the Diagnosis of Melanoma In Situ in Sun-Damaged Skin.

ABSTRACT: Histologic differentiation between melanoma in situ in chronically sun-damaged skin (CSDS) [lentigo maligna (LM)] and CSDS without malignancy is difficult because signs of melanocyte activation and proliferation are found in both. A potentially reliable and quantifiable criterion is melanocyte density (MD). Here, we evaluated whether and to what extent MD allows the distinction between LM and CSDS, which is particularly relevant for the evaluation of borderline cases and surgical margins.Articles assessing MD in LM and/or CSDS were evaluated in a systematic review. The results were categorized and compared according to staining. Cutoff values were included whenever stated.Twenty articles matched the selection criteria. Six hundred forty-four samples of CSDS and 227 samples of LM were considered. In each individual study, mean MD scores were higher for LM than for CSDS. However, looking at the overall study situation, it becomes clear that the data are very heterogeneous and show overlaps. Therefore, no reliable orientation value can be derived. Only 1 article defined a cutoff value.The data of MD in LM in contrast to CSDS were sparse, and a defined cutoff value was only mentioned in 1 article for microphthalmia-associated transcription factor, which cannot yet be generalized. Especially regarding the importance for the definition of surgical resection margins, this unsatisfactory data set highlights the need for further studies. More precise diagnostic criteria could spare some patients extensive and possibly disfiguring surgery.

From mice to men: An assessment of preclinical model systems for the study of vitiligo.

Vitiligo is an autoimmune skin disease of multiple etiology, for which there is no complete cure. This chronic depigmentation is characterized by epidermal melanocyte loss, and causes disfigurement and significant psychosocial distress. Mouse models have been extensively employed to further our understanding of complex disease mechanisms in vitiligo, as well as to provide a preclinical platform for clinical interventional research on potential treatment strategies in humans. The current mouse models can be categorized into three groups: spontaneous mouse models, induced mouse models, and transgenic mice. Despite their limitations, these models allow us to understand the pathology processes of vitiligo at molecule, cell, tissue, organ, and system levels, and have been used to test prospective drugs. In this review, we comprehensively evaluate existing murine systems of vitiligo and elucidate their respective characteristics, aiming to offer a panorama for researchers to select the appropriate mouse models for their study.

Diagnostic and therapeutic considerations in patients with bilateral diffuse uveal melanocytic proliferation.

PURPOSE: This review aims to summarize the current knowledge concerning the clinical features, diagnostic work-up, and therapeutic approach of bilateral diffuse uveal melanocytic proliferation (BDUMP). METHODS: A meticulous literature search was performed in the PubMed database. A supplementary search was made in Google Scholar to complete the collected items. Our search strategy utilized the following keywords: "bilateral diffuse uveal melanocytic proliferation", "BDUMP", and "Paraneoplastic Syndrome". Articles were considered based on their relevance, with the search spanning publications up to 2023. Studies were excluded if they did not contribute pertinent information or lacked methodological rigor. A critical appraisal of included studies was conducted, assessing study design, sample size, methodology, and potential bias, ensuring a thorough and transparent review process. RESULTS: BDUMP is a rare and potentially sight-threatening condition characterized by the bilateral proliferation of melanocytes within the uvea. BDUMP is typically observed in middle-aged or elderly individuals and is often associated with an underlying malignancy, most commonly of gastrointestinal origin. BDUMP is frequently misdiagnosed as a benign nevus or choroidal metastasis, leading to delayed diagnosis and treatment. The ophthalmic symptoms and signs typically precede the diagnosis of a systemic malignancy, emphasizing the crucial role of ophthalmologists in the recognition of BDUMP. Several diagnostic modalities can aid in the diagnosis of BDUMP, including ophthalmic examination, imaging studies such as optical coherence tomography, fluorescein angiography, and indocyanine green angiography, and biopsy of the uveal tissue. Treatment of BDUMP is directed towards the underlying malignancy and may include chemotherapy, radiotherapy, or surgical resection. Additionally, strict monitoring with regular follow-ups may contribute to the detection of new lesions and the reduction in the size of existing ones. CONCLUSIONS: BDUMP can be considered a potential biomarker in the management of malignancies, especially when the primary underlying tumor has not been detected. Further research is needed to better understand the pathogenesis of BDUMP and its association with malignancy.

Amplification of Mutant NRAS in Melanocytic Tumors With Features of Spitz Tumors.

NRAS activating mutations are prevalent in melanocytic neoplasia, occurring in a subset of common acquired melanocytic nevi and ∼30% of cutaneous melanomas. In this study, we described a cohort of 7 distinctive melanocytic tumors characterized by activating point mutations in codon 61 of NRAS with amplification of the mutant NRAS allele and shared clinicopathologic features. These tumors occurred predominantly in younger patients, with a median age of 20 years (range, 6-56 years). They presented as papules on the helix of the ear (4 cases) or extremities (3 cases). Microscopically, the tumors were cellular, relatively well-circumscribed, compound, or intradermal proliferations. The tumor cells often extended into the deep reticular dermis and involved the superficial subcutaneous fat in some cases. The melanocytes were epithelioid to spindled with moderate amounts of cytoplasm and conspicuous nucleoli. They were arranged in short plexiform fascicles, nests, and cords. Some cases had occasional pleomorphic and multinucleated melanocytes. Rare dermal mitotic figures were present in all cases. The dermis contained thick collagen bundles and minimal solar elastosis. Follow-up data were available for 5 patients, with a median period of 4.2 years (range, 1-9 years), during which no recurrences or metastases were reported. Our series highlights a clinicopathologically and molecularly distinctive subset of NRAS-mutated tumors with amplification of the mutant NRAS allele.

Thickness of melanocytes in giant congenital melanocytic nevus for complete surgical excision: clinicopathological evaluation of 117 lesions according to the area and size.

BACKGROUND: Giant congenital melanocytic nevi (GCMN) are usually defined as nevi that exceed 20 cm in maximal diameter or 15% of the total body surface area. There have been reports of life-long malignant change risks arising from GCMN, leading to surgical excision of GCMN. This study aims to evaluate the thickness of melanocytes based on clinical factors in order to provide objective information for the complete resection of the lesion. METHODS: Overall, 75 patients diagnosed with GCMN between 2000 and 2021 were included, and their clinical records were collected retrospectively. 117 pathologic slides obtained during excision were reviewed to measure nevus thickness. Clinical factors were assessed with a generalized estimated equation model for association with nevus thickness. RESULTS: The thickness of nevus was significantly associated with the location and size. Nevus thickness was more superficial in the distal extremity than in the head and trunk (P = 0.003 [head]; P < 0.001 [trunk]; P = 0.091 [Proximal extremity]). Nevi sized 60 cm or more were significantly deeper than those measuring 20-29.9 cm (P = 0.035). An interaction between size and location existed (P < 0.001). Trunk and distal extremity lesions consistently exhibited uniform thickness regardless of lesion size, whereas head and proximal extremity lesions showed variations in thickness based on lesion size. CONCLUSION: GCMNs have differences in thickness according to location and size. Therefore, it is necessary to devise an approach optimized for each patient to treat GCMN. In the study, it was emphasized that the thickness of GCMN is correlated with clinical factors, specifically the location and size of the nevus. Consequently, these findings underscore the need for individualized treatment plans for effective surgical intervention.

Optimized self-attention based cycle-consistent generative adversarial network adopted melanoma classification from dermoscopic images.

Skin is the exposed part of the human body that constantly protected from UV rays, heat, light, dust, and other hazardous radiation. One of the most dangerous illnesses that affect people is skin cancer. A type of skin cancer called melanoma starts in the melanocytes, which regulate the colour in human skin. Reducing the fatality rate from skin cancer requires early detection and diagnosis of conditions like melanoma. In this article, a Self-attention based cycle-consistent generative adversarial network optimized with Archerfish Hunting Optimization Algorithm adopted Melanoma Classification (SACCGAN-AHOA-MC-DI) from dermoscopic images is proposed. Primarily, the input Skin dermoscopic images are gathered via the dataset of ISIC 2019. Then, the input Skin dermoscopic images is pre-processed using adjusted quick shift phase preserving dynamic range compression (AQSP-DRC) for removing noise and increase the quality of Skin dermoscopic images. These pre-processed images are fed to the piecewise fuzzy C-means clustering (PF-CMC) for ROI region segmentation. The segmented ROI region is supplied to the Hexadecimal Local Adaptive Binary Pattern (HLABP) to extract the Radiomic features, like Grayscale statistic features (standard deviation, mean, kurtosis, and skewness) together with Haralick Texture features (contrast, energy, entropy, homogeneity, and inverse different moments). The extracted features are fed to self-attention based cycle-consistent generative adversarial network (SACCGAN) which classifies the skin cancers as Melanocytic nevus, Basal cell carcinoma, Actinic Keratosis, Benign keratosis, Dermatofibroma, Vascular lesion, Squamous cell carcinoma and melanoma. In general, SACCGAN not adapt any optimization modes to define the ideal parameters to assure accurate classification of skin cancer. Hence, Archerfish Hunting Optimization Algorithm (AHOA) is considered to maximize the SACCGAN classifier, which categorizes the skin cancer accurately. The proposed method attains 23.01%, 14.96%, and 45.31% higher accuracy and 32.16%, 11.32%, and 24.56% lesser computational time evaluated to the existing methods, like melanoma prediction method for unbalanced data utilizing optimized Squeeze Net through bald eagle search optimization (CNN-BES-MC-DI), hyper-parameter optimized CNN depending on Grey wolf optimization algorithm (CNN-GWOA-MC-DI), DEANN incited skin cancer finding depending on fuzzy c-means clustering (DEANN-MC-DI). RESEARCH HIGHLIGHTS: This manuscript, self-attention based cycle-consistent. SACCGAN-AHOA-MC-DI method is implemented in Python. (SACCGAN-AHOA-MC-DI) from dermoscopic images is proposed. Adjusted quick shift phase preserving dynamic range compression (AQSP-DRC). Removing noise and increase the quality of Skin dermoscopic images.

Perineural differentiation in neurotized nevi.

BACKGROUND: Perineuriomatous melanocytic nevi are rare and this may indicate the similar embryological source of melanocytes and peripheral nerves in the neural crest. Neurotized melanocytic nevi may resemble nerve sheath tumors histologically, and show schwannian differentiation. However, literature on whether neurotized nevi differentiate into perineural cells is controversial. We examined our cases of neurotized nevi for evidence of perineural differentiation. MATERIALS AND METHODS: A total of 100 benign nevi with large neurotized component (microscopically involved a low power field 4.2 mm in diameter) were prospectively evaluated in excisional biopsy samples. Immunohistochemical stainings for EMA, Claudin1, Glut1 and neurofilament were performed. RESULTS: Perineural differentiation was immunohistochemically detected in the neurotized component of the nevi in 61% of the cases with EMA and in all the cases with Glut1 and Claudin1. Axonal differentiation was not detected with neurofilament. The expression pattern, especially with Glut1, was usually in form of partial or complete staining surrounding the Meissner's corpuscle-like structure (MCLS). Also, a linear/curvilinear staining pattern was observed particularly with Claudin1. A diffuse staining pattern with EMA, Glut1 and Claudin1 was detected in a case with a microscopically distinct whorl structure, and in which spindle cells are separated from the superficial epithelioid melanocytes with an abrupt transition histologically. These findings of the case are compatible with previous reports of perineuromatous nevus. CONCLUSION: Perineural differentiation is not uncommon and immunohistochemically observed in all nevi with a relatively large component of neurotization. To prevent misdiagnosing desmoplastic melanoma and overtreating patients, it is crucial to be aware of perineuromatous nevi.

The clinico-pathological spectrum of plaque-type blue naevi and their potential for malignant transformation.

AIMS: Plaque-type blue naevi are rare melanocytic tumours presenting as large, pigmented plaques at birth or during childhood. There is a risk for malignant transformation, but no larger comprehensive studies exist and the diagnosis is challenging, especially on limited biopsy material. The aim is to describe the clinicopathological features and behaviour of the disease more comprehensively. METHODS AND RESULTS: We retrieved eight plaque-type blue naevi, presenting as large, pigmented plaques (median = 7 cm; range = 3-26) most frequently affecting the scalp (four) followed by the cheek, arm, abdominal wall and gluteal cleft (one each), with a slight female predilection. Median age at time of biopsy was 39.5 years (range = 15-90), but three tumours had been present at birth and one since childhood. Histopathologically, the tumours were poorly circumscribed and composed of cellular fascicles of uniform spindle cells in a background of variably prominent pigmented dendritic cells affecting dermis and subcutaneous tissues. The majority had mutations in GNAQ. One tumour showed malignant transformation, characterised by an expansile nodule of pleomorphic epithelioid melanocytes with rhabdoid morphology, high mitotic activity and areas of necrosis. This patient developed metastatic melanoma to lymph nodes. All patients are alive with a median follow-up of 60 months. CONCLUSION: Plaque-type blue naevi are diagnostically challenging tumours with risk for malignant transformation. Awareness and familiarity with the salient clinicopathological features are necessary for reliable diagnosis, and long-term clinical follow-up is required to monitor for malignant transformation.

Vitiligo non-responding lesions to narrow band UVB have intriguing cellular and molecular abnormalities that may prevent epidermal repigmentation.

We have discovered that human vitiligo patients treated with narrow-band UVB (NBUVB) demonstrated localized resistance to repigmentation in skin sites characterized by distinct cellular and molecular pathways. Using immunostaining studies, discovery-stage RNA-Seq analysis, and confirmatory in situ hybridization, we analyzed paired biopsies collected from vitiligo lesions that did not repigment after 6 months of NBUVB treatment (non-responding) and compared them with repigmented (responding) lesions from the same patient. Non-responding lesions exhibited acanthotic epidermis, had low number of total, proliferative, and differentiated melanocyte (MC) populations, and increased number of senescent keratinocytes (KCs) and of cytotoxic CD8+ T cells as compared with responding lesions. The abnormal response in the non-responding lesions was driven by a dysregulated cAMP pathway and of upstream activator PDE4B, and of WNT/ß-catenin repigmentation pathway. Vitiligo-responding lesions expressed high levels of WNT10B ligand, a molecule that may prevent epidermal senescence induced by NBUVB, and that in cultured melanoblasts prevented the pro-melanogenic effect of α-MSH. Understanding the pathways that govern lack of NBUVB-induced vitiligo repigmentation has a great promise in guiding the development of new therapeutic strategies for vitiligo.

Comparative outcomes of autologous cultured melanocytes transplantation and non-cultured epidermal cell suspension transplantation in piebaldism patients: A retrospective study.

PURPOSE: To compare the efficacy and safety of autologous cultured melanocytes transplantation (CMT) and non-cultured epidermal cell suspension transplantation (NCES) in the treatment of piebaldism. PATIENTS AND METHODS: A retrospective study was conducted on 30 anatomically based lesions from nine piebaldism patients who underwent either CMT (n = 7) or NCES (n = 23) between 2018 and 2020. The extent of repigmentation and colour matching was evaluated in all recipient sites using a digital imaging analysis system. In addition, adverse effects have also been assessed by follow-up results. RESULTS: More than 75% repigmentation was achieved in 100% (7/7) and 60.9% (14/23) of the 30 lesions with the CMT and NCES, respectively. There were significant differences between the two methods in terms of repigmentation. The majority of patients had colour mismatches, and there was no discernible difference between the two surgical techniques. Adverse reactions rarely occurred. CONCLUSION: The present study suggested that autologous CMT may provide better repigmentation in piebaldism patients than NCES with no significant side effects.

Diagnostic utility of the 23-gene expression profile test for an atypical intradermal melanocytic proliferation.

Ancillary tests such as immunohistochemistry (IHC) and gene expression profile (GEP) testing may be needed to arrive at a definitive diagnosis for some atypical melanocytic neoplasms. A 34-year-old male with a family history of melanoma presented with a large, heterogeneous melanocytic lesion on the cheek. Histopathological review of two biopsies revealed an atypical intradermal melanocytic proliferation with spitzoid features without ulceration or regression. Scattered mitotic figures were identified. In addition to performing SOX10 IHC, PRAME and HMB45 staining highlighted weak, patchy positivity that was stronger in superficial, pleomorphic melanocytes (Ki-67, 5-7% mitotic rate). Based on these concerning but ambiguous IHC results and lingering concern for melanoma reiterated by other consulting dermatopathologists, the 23-GEP was requested for both specimens, which both returned a malignant result. The inconclusive histopathological features of malignancy were resolved by 23-GEP testing, facilitating a final diagnosis of malignant melanoma (pT3a, 2.5 mm Breslow depth, Clark's level IV).

Blaschkoid melanotic cutaneous lupus erythematosus with "melanocytic nests".

Melanotic cutaneous lupus erythematosus (LE) is a newly described clinical variant of chronic cutaneous LE, presenting with localized or diffuse brownish or grayish macular and reticulated pigmentation in the absence of erythema, scaling, atrophy, scarring, or telangiectasia. The diagnosis is based upon histopathology, which demonstrates the characteristic features of LE with an interface vacuolar dermatitis with melanophages, and a superficial and deep, perivascular and periadnexal lymphocytic infiltrate with mucin deposition. Herein, we describe a case of a 61-year-old White male presenting with melanotic cutaneous LE with a blaschkoid distribution on his face in which the histopathological phenomenon of "true melanocytic nests" in the setting of a lichenoid pattern was seen. We want to highlight how nests of cellular aggregates at the dermoepidermal junction labeling with melanocytic markers may occur in the setting of an interface tissue reaction. This benign reactional pattern may mimic atypical melanocytic proliferations, especially on sun-damaged skin. Clinicopathological correlation and careful microscopic examination using a panel of multiple melanocytic markers is crucial for making an accurate final diagnosis. All the cases of melanotic cutaneous LE reported in the literature are also reviewed.

Intraoperative View of a Multinodal, Paralysis-Inducing Spinal Melanocytoma: Case Report and Literature Review.

Melanocytomas arising from the leptomeningeal melanocytes within the central nervous system are a rare occurrence, accounting for 0.06%-0.1% of brain tumors and having an incidence of 1/10 million people per year.1-14 Here, we describe the case of 68-year-old male presenting with bilateral lower extremity weakness progressing to paralysis and urinary incontinence (Video 1). Upon examination, this gentleman had no sensation below T11. Magnetic resonance imaging showed multiple contrast-enhancing lesions with a major intradural lesion at level T11 arising from the ventrolateral surface and causing severe spinal cord compression. The multifocal nature of this tumor further adds to its rarity. Interdisciplinary indication for surgical resection of the intradural lesion was made. This was accomplished through a T11 laminectomy and concomitant T11-12 stabilization with neuromonitoring. Pathologic analysis of the resected tumor identified an S100+, HMB45+, pigmented melanocytoma. No complications occurred during the procedure. The patient was discharged to rehabilitation with persistent neurologic deficits. Routine follow-up is indicated given the high rates of recurrence and the multiple remaining tumor nodules.14.

Immunohistochemistry Update in Dermatopathology and Bone and Soft Tissue Pathology.

CONTEXT.­: Immunohistochemistry plays an important role in dermatopathology, particularly for melanocytic lesions and poorly differentiated malignancies. In the field of bone and soft tissue pathology, molecular methods remain the gold standard for diagnosis; however, immunohistochemistry targeting underlying molecular alterations represents a valuable screening tool, especially in areas with limited access to molecular testing. OBJECTIVE.­: To describe the utility and limitations of new and emerging immunohistochemical stains in the diagnosis of skin, soft tissue, and bone tumors. DATA SOURCES.­: A literature review of recently described immunohistochemical stains in the fields of dermatopathology and bone and soft tissue pathology was performed. CONCLUSIONS.­: Immunohistochemistry is an important adjunctive tool for select entities in dermatopathology and bone and soft tissue pathology, and it provides pathologists with valuable evidence of their behavior, underlying molecular alterations, and line of differentiation. Furthermore, immunostains targeting molecular abnormalities have the potential to replace current molecular methods. Many of these recently described stains demonstrate higher sensitivity and specificity; however, limitations and pitfalls still exist, and correlation with morphologic and clinical findings remains essential for diagnosis.

Active natural compounds perturb the melanoma risk-gene network.

Cutaneous melanoma is an aggressive type of skin cancer with a complex genetic landscape caused by the malignant transformation of melanocytes. This study aimed at providing an in silico network model based on the systematic profiling of the melanoma-associated genes considering germline mutations, somatic mutations, and genome-wide association study signals accounting for a total of 232 unique melanoma risk genes. A protein-protein interaction network was constructed using the melanoma risk genes as seeds and evaluated to describe the functional landscape in which the melanoma genes operate within the cellular milieu. Not only were the majority of the melanoma risk genes able to interact with each other at the protein level within the core of the network, but this showed significant enrichment for genes whose expression is altered in human melanoma specimens. Functional annotation showed the melanoma risk network to be significantly associated with processes related to DNA metabolism and telomeres, DNA damage and repair, cellular ageing, and response to radiation. We further explored whether the melanoma risk network could be used as an in silico tool to predict the efficacy of anti-melanoma phytochemicals, that are considered active molecules with potentially less systemic toxicity than classical cytotoxic drugs. A significant portion of the melanoma risk network showed differential expression when SK-MEL-28 human melanoma cells were exposed to the phytochemicals harmine and berberine chloride. This reinforced our hypothesis that the network modeling approach not only provides an alternative way to identify molecular pathways relevant to disease but it may also represent an alternative screening approach to prioritize potentially active compounds.

Re-examining the evidence that ivermectin induces a melanoma-like state in Xenopus embryos.

Modeling metastasis in animal systems has been an important focus for developing cancer therapeutics. Xenopus laevis is a well-established model, known for its use in identifying genetic mechanisms underlying diseases and disorders in humans. Prior literature has suggested that the drug, ivermectin, can be used in Xenopus to induce melanocytes to convert into a metastatic melanoma-like state, and thus could be ideal for testing possible melanoma therapies in vivo. However, there are notable inconsistencies between ivermectin studies in Xenopus and the application of ivermectin in mammalian systems, that are relevant to cancer and melanoma research. In this review, we examine the ivermectin-induced phenotypes in Xenopus, and we explore the current uses of ivermectin in human research. We conclude that while ivermectin may be a useful drug for many biomedical purposes, it is not ideal to induce a metastatic melanocyte phenotype in Xenopus for testing the effects of potential melanoma therapeutics.

The Skin Molecular Ecosystem Holds the Key to Nevogenesis and Melanomagenesis.

Early detection of melanoma is critical to good patient outcomes, but we still know little about the mechanisms of early melanoma development. Normal epidermis has many of the sequence variants and genetic architecture disruptions found in both benign nevi, melanomas, and other skin cancers, yet continues to behave more or less normally. One hypothesis is that many melanocytes in this context are "tumor competent" but are regulated by the microenvironment provided by the surrounding keratinocytes to inhibit progress to nevi or melanoma. There is evidence of accumulating disorder in several measures of the genomic and epigenomic landscape from normal skin through nevi to melanoma that may be key to promoting nevogenesis and melanomagenesis.